FR2848555A1 - New (-) enantiomer of tenatoprazole used as proton pump inhibitor in treating digestive disorders - Google Patents

Abstract

(-)-Tenatoprazole (I) and its salts, are new. An Independent claim is also included for the preparation of (I).

Description

The present invention relates to tenatoprazole, and more

  particularly an enantiomer of tenatoprazole, a process for its preparation, as well as its use in human or veterinary therapy.

  Tenatoprazole, i.e. 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2pyridyl) methyl] sulfinyl] imidazo [4,5-b] pyridine, is described in Patent EP 254,588. ' It is one of the drugs considered to be proton pump inhibitors, i.e. drugs which inhibit the secretion of gastric acid and are useful for the treatment of gastric and duodenal ulcers. It can also be used in the treatment of gastroesophageal reflux, digestive hemorrhages and dyspepsias, because of its relatively long elimination half-life, as indicated in French patent application FR 02.13113.

  The first known derivative of the proton pump inhibitor series is omeprazole, described in patent EP 001,529, which has inhibitory properties for gastric acid secretion, and is widely used as an anti-ulcer in human therapy.

  In addition to omeprazole, other proton pump inhibitors are well known and mention may be made in particular of rabeprazole, pantoprazole, lansoprazole, all of which have a structural analogy and belong to the group of pyridinyl-methyl-sulfinyl -benzimidazoles. These compounds are sulfoxides having an asymmetry at the level of the sulfur atom and are therefore generally present in the form of a racemic mixture of two enantiomers.

  Like omeprazole and other sulfoxides with a similar structure, tenatoprazole has an asymmetric structure and can therefore be in the form of the racemic mixture or its enantiomers. Thus, it can exist in the form of its two enantiomers having the configurations R and S, or (+) or (-), respectively.

  Recent work has shown that, unlike all other proton pump inhibitors such as, for example, omeprazole or lansoprazole, and unexpectedly, tenatoprazole has a markedly prolonged duration of action, resulting from '' a plasma half-life approximately 7 times higher. Thus, the medical data collected show that tenatoprazole brings a level of symptom relief and healing of gastric lesions greater than that of other drugs 10 belonging to the same therapeutic class of proton pump inhibitors, which then allows its use. effective in the treatment of atypical and esophageal symptoms of gastroesophageal reflux, digestive hemorrhage and dyspepsia, as noted above.

  The studies carried out by the applicant have made it possible to show that each of the two enantiomers contributes in a different way to the properties of tenatoprazole and that the two enantiomers (+) and (-) have significantly different pharmacokinetic properties. Thus, it is possible to prepare drugs with specific action by isolating the enantiomers, and these enantiomers themselves have a different pharmacokinetic profile than that of the known racemic mixture. It thus becomes possible to use each of these enantiomers more effectively in precise indications for the treatment of perfectly identified pathologies.

  The present invention therefore relates to the (-) configuration enantiomer of tenatoprazole, and its use in human or veterinary therapy.

  The invention also relates to a pharmaceutical composition comprising the (-) enantiomer of tenatoprazole combined with one or more pharmaceutically acceptable excipients and carriers.

  The invention also relates to the use of the (-) enantiomer of tenatoprazole in the manufacture of a medicament for the treatment of digestive pathologies where an inhibition of acid secretion must be intense and prolonged for the treatment of symptoms and lesions of gastroesophageal reflux, digestive haemorrhage resistant to other proton pump inhibitors, as well as for the treatment of these diseases in multi-drug patients.

  A further subject of the invention is the use of the (-) enantiomer of tenatoprazole for the manufacture of a medicament having improved pharmacokinetic properties allowing a dosage of a single medication intake per day in the relevant indications, such as indicated below, in particular for the eradication of Helicobacter pylori in the treatment of duodenal ulcers, which require two doses, morning and evening, with the other 15 proton pump inhibitors.

  Finally, the subject of the invention is a process for preparing the (-) enantiomer of tenatoprazole.

  The (-) enantiomer of tenatoprazole can be used in the form of a salt, in particular an alkali metal or alkaline earth metal salt, and for example in the form of a sodium, potassium, lithium, magnesium or calcium salt. These salts can be obtained from the (-) enantiomer of tenatoprazole previously isolated, by a salification reaction according to a method customary in the art, for example by the action of basic mineral reagents containing alkali or alkaline-earth counter ions.

  Tenatoprazole can be represented by the following general formula OMe H H3C CH3

N O

  OH3C N NN The (-) enantiomer according to the present invention can be obtained in optically pure form simply from the racemic mixture, by any suitable separation method, and more particularly by a preparative column chromatography method, for example by chiral chromatography or HPLC. By "optically pure form" is meant that the (-) enantiomer is substantially free of or only contains traces of the (+) enantiomer. If appropriate, base salification is then carried out in an appropriate solvent, to form a salt, in particular an alkali or alkaline earth metal salt.

  The principle of the chiral chromatography method is based on the difference in affinity between the (+) and (-) enantiomers and the chiral selector of the stationary phase. This method makes it possible to separate the enantiomers with a good yield.

  The (-) enantiomer of tenatoprazole corresponds to (-) - 5methoxy-2 - [[(4methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] imidazo [4,5-b] pyridine, or ( -) - tenatoprazole. This shape can be determined by optical rotation measurements according to the usual techniques.

  For example, one can prepare a 0.25% solution of the desired enantiomer (50 mg of sample for 20 ml of solvent) dissolved in DMF or in acetonitrile and using a polarimeter of the type commonly used (Jobin Yvon). Thus, the optical angle of rotation of (-) - tenatoprazole is levorotatory in dimethylformamide and in acetonitrile, and its melting point is 130 C (decomposition).

  The racemic mixture used as starting material can be obtained by known methods, for example according to the method described in patent EP 254,588. Thus, it can be prepared by treating with an oxidizing agent, such as a perbenzoic acid, the corresponding sulfide originating from the condensation of a thiol and a pyridine, preferably in the presence of a base such as potassium hydroxide in a suitable solvent, for example ethanol, hot.

  The method of separation of the enantiomers from the racemic by high performance liquid chromatography (HPLC) makes it possible to isolate the (-) enantiomer with excellent purity (chiral purity: min. 98.8% of area).

  Unexpectedly, studies carried out on the enantiomer prepared as indicated above have revealed pharmacokinetic properties which are fundamentally different from those of conventional proton pump inhibitors and from those of racemic tenatoprazole, making it possible to envisage its use in specific indications. Thus, the racemic mixture and the (-> isomer of tenatoprazole differ significantly by their pharmacokinetic properties, as shown by the studies described below. This characteristic is essential because it makes it possible to provide the practitioner with a drug specifically suitable for the effective treatment of specific pathologies.

  More particularly, the different pharmacokinetic properties of the (-) isomer appeared during a pharmacokinetic study in Caucasians at doses of 10, 20, 40, 80 and 120 mg.

  Given the variability of the pharmacokinetic parameters, in particular AUCoif (area under the curve) and tl / 2 (elimination half-life), certain subjects have been genotyped so as to identify the type of metabolizer, slow or fast, to which it belongs . In parallel, a chiral pharmacokinetic study was undertaken to assess the preponderance of the pharmacokinetics of the (-) isomer in the pharmacokinetics of racemic tenatoprazole.

  The major problem in the metabolism of proton pump inhibitors, in general, is that they are largely metabolized by cytochrome 2C19, which is under the control of chromosome 10 and thus exhibit a genetic polymorphism, that is to say a variable activity depending on the type of patient population. This results in variable plasma levels as well as a susceptibility to possible harmful drug interactions, depending on the individual.

  It is clear that homozygous subjects with a mutation in exon 5 leading to the CYP2C19 * 2 / * 2 genotype have pharmacokinetic characteristics that are totally different from the standard population. These 10 subjects have a very weak metabolic activity affecting CYP2Cl9 responsible in part for the metabolism of tenatoprazole.

  Analysis of the plasma after chiral separation showed that these subjects had a very significant increase in the (+) isomer compared to the (->) isomer. These subjects are described as slow metabolizers.

  Conversely, fast metabolizing subjects, characterized by the CYP2C19 * 1 / * 1 genotype, have a higher concentration of (-) isomer than (+) isomer.

  Thus, the (+) isomer is metabolized by a preponderant 20 pathway, CYP2Cl9, while the (-) isomer is metabolized by 2 pathways, namely CYP2Cl9 and CYP3A4.

  These observations lead to proposing the isolation and administration of a single isomer, the (-) isomer which has the following advantages: - a reduction in inter-subject variability o better use of the product with a lower more homogeneous response to treatment, - better impregnation of the product, because the elimination rate is slower and the mean time of presence in the body (MRT) is longer, - a decrease the number of drug interactions with potentially co-administered drugs. Indeed, the (-) isomer is metabolized by two pathways, cytochromes 2C19 and 3A4, which makes it possible to compensate for a possible deficit or blockage of cytochrome 2C19, - simple use in all types of patients whether they are slow or fast metabolizers. Indeed, the (-) isomer in the slow metabolizing subject will be metabolized by CYP3A4, which makes it possible to obtain uniform pharmacokinetic parameters whatever the patients, whether they are slow or rapid metabolizers.

  Furthermore, the isolation of the (-) enantiomer made it possible to determine a pharmacokinetic profile different from that of the racemic, in particular an average plasma half-life of between 10 and 12 hours approximately for the (-) enantiomer for doses of 20 mg to 80 mg. Conversely, the racemic has an average plasma half-life around 7 hours at a dose of 20 mg and 9 hours at a dose of 80 mg.

  These significantly different properties, which are added to the pharmacological properties found in the racemic mixture, and well known in the pharmacotherapeutic class of proton pump inhibitors, in particular the inhibitory activity of H ± K ± ATPase pumps on the gastric secretion, show that the (-) enantiomer of tenato20 prazole can be advantageously used in the treatment of digestive pathologies where it is necessary to obtain an inhibition of intense and prolonged acid secretion, such as Barrett's syndromes which represent attacks Pre-cancerous reflux disease for which the risk of esophageal adenocarcinoma is directly proportional to the frequency, severity and duration of episodes of gastroesophageal reflux.

  The (-) enantiomer of tenatoprazole is also suitable for the treatment of Zollinger-Ellison syndrome and other acid hypersecretion syndromes, and the treatment of atypical and esophageal symptoms of gastroesophageal reflux, digestive hemorrhage resistant to other pump inhibitors protons, as well as for the treatment of these diseases in multi-drug patients, in particular in patients receiving treatments involving the administration of several drugs, and more particularly elderly patients, in order to avoid incidents related to drug interaction.

  The (-) enantiomer of tenatoprazole can also be used, preferably in combination with one or more antibiotics, in the treatment of ulcers in the event of infection by Helicobacter pylori, in particular for the eradication of Helicobacter pylori for promote healing of the duodenal ulcer and for the prevention of any recurrence. 10 The (-) enantiomer of tenatoprazole, in the treatment of the pathologies indicated above, and very particularly in the treatment of Barrett and ZollingerEllison syndromes and gastroesophageal reflux disease, digestive hemorrhages, can be administered in the forms usual adapted to the chosen mode of administration, for example by oral or parenteral route, preferably by oral or intravenous route. It is possible, for example, to use formulations of tablets or capsules containing the (-) enantiomer of tenato20 prazole as active ingredient, or alternatively oral solutions or emulsions or solutions for parenteral administration containing a tenatoprazole salt with a usual pharmaceutically acceptable carrier. . The (-) enantiomer salt of tenatoprazole can be chosen, for example, from sodium, potassium, lithium, magnesium or calcium salts.

  By way of example, an appropriate formulation of tablets containing 20 mg of the (-) isomer of tenatoprazole combined with pharmaceutically acceptable carriers and excipients is indicated below: (-) - t-atoprazole 30.0 mg lactose 40 0.0 mg aluminum hydroxide 17.5 mg hydroxvpropylcellulose 8.0 mg talc 4.5 mg titanium dioxide 5.0 mg magnesium stearate 2.0 mg usual excipients qs 160.0 mg An example of a gastric-resistant enteric capsule formulation (walls based on acetophthalate derivatives, polyvinylpyrrolidone, and acrylic resins) of size 2, containing 40 mg of (-) isomer of tenatoprazole is indicated below: ( -) - tenatoprazole 40.0 mg lactose 200.0 mg magnesium stearate 10.0 mg The dosage is determined by the practitioner depending on the patient's condition and the severity of the condition. It is generally between 10 and 120 mg, preferably between 20 and 40 mg, of (-) enantiomer of tenatoprazole per day. For example, it can be administered at a dose of 1 to 2 unit doses, for example tablets, each containing 10 to 80 mg, preferably 20 to 40 mg, of active ingredient per day for a period time which can be between 4 and 12 weeks, in the case of an attack or maintenance treatment. In the case of a pediatric form suitable for young children, for example in the form of an oral solution, the unit dose may be lower, for example 2 or 5 mg. In the case of severe conditions, it may be effective to administer the drug first intravenously and then orally. The invention also has the advantage of allowing efficient sequential treatment by simple administration of a single tablet dosed at or 80 mg per week.

  One of the advantages of the present invention is that it allows the treatment of the pathologies indicated above with a dosage limited to a single drug intake per day, including in the treatment of duodenal ulcer resulting from Helicobacter infection. pylori, unlike conventional drugs, including conventional proton pump inhibitors which require two daily doses. An example of the preparation of the (-) enantiomer of tenatoprazole is described below in order to illustrate the present invention.

Example

  The preparative chromatography conditions, given by way of example, are as follows: Column: 265 x 110 mm ChiralPak Chiral stationary phase selector of the amylose tris type ((S) -a-methylbenzylcarbamate] Flow rate: 570 ml / min Detection : UV 240 nm Temperature: Ambient These conditions are implemented on a liquid preparative chromatography apparatus.

  About 2 g of racemic mixture of tenatoprazole having a purity greater than 99.5% are introduced.

  The (-) enantiomer is identified by measuring the angle of optical rotation which must be levorotatory. This measurement can be made directly on the column, the product being dissolved in the solvent (acetonitrile).

Claims (13)

  1. (-) - tenatoprazole, or (-) - 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2pyridyl) methyl] sulfinyl] imidazo [4,5-b] pyridine or a of its salts.   2. Process for the preparation of (-) - tenatoprazole according to claim 1, characterized in that it consists in carrying out preparative column chromatography, in particular chiral chromatography or HPLC, on the racemic mixture.   3. Method according to claim 2, characterized in that the (-) - tenatoprazole is salified by the action of basic mineral reagents comprising against alkaline or alkaline-earth ions. 4. Pharmaceutical composition, characterized in that it comprises (-) - tenatoprazole, or (-) - 5-methoxy-2 [[((4-methoxy-3,5dimethyl-2-pyridyl) methyl] sulfinyl] imidazo15 [ 4,5-b] pyridine or a salt thereof, and one or more pharmaceutically acceptable excipients or carriers.   5. Composition according to claim 4, characterized in that the (-) - tenatoprazole is in the form of an alkali or alkaline earth metal salt.   6. Composition according to claim 5, characterized in that the (-) - tenatoprazole is under sodium salt, potassium, lithium, magnesium or calcium.   7. Composition according to any one of claims 4 to 6, characterized in that it is in the form of a unit dose containing 10 to 80 mg of active principle.   8. The use of (-) - tenatoprazole for the treatment of digestive pathologies.   9. The use of (-) - tenatoprazole for the manufacture of a medicament for the treatment of digestive pathologies where an inhibition of acid secretion must be intense and prolonged.   10. The use of (-) - tenatoprazole for the manufacture of a medicament for the treatment of Barrett's syndromes, atypical and esophageal symptoms of gastroesophageal reflux, and digestive bleeding resistant to other proton pump inhibitors .   11. The use of (-) - tenatoprazole for the manufacture of a medicament for the treatment of digestive pathologies, gastroesophageal reflux, and digestive hemorrhages, in polymedicated patients.   12. The use of (-) - tenatoprazole in combination with one or more antibiotics for the manufacture of a medicament for the treatment of duodenal ulcer resulting from infection with Helicobacter pylori.   13. The use of (-) - tenatoprazole for the manufacture of a medicinal product with improved pharmacokinetic properties.